1. Field of the Invention
This invention resides in the field of chelating agents and medical uses of such agents. This invention also resides in the field of treatments for ischemia, seizures and trauma. All literature and patent citations in this specification are hereby incorporated herein by reference.
2. Description of the Prior Art
Iron and copper cations are known to catalyze hydroxy free radical formation in Haber-Weiss pathways. Hydroxy free radicals themselves are known to produce tissue damage. Iron and copper cations are released from tissues during ischemia and in association with a variety of disease processes.
Attempts to mitigate the catalytic effectiveness of iron and copper cations by administering iron chelating siderophores such as deferoxamine to form complexes with these cations have not been unequivocally successful in inhibiting tissue damage from hydroxy free radicals in vivo. Siderophores such as deferoxamine are poor chelators for copper cations. Although present in the body in much lower concentrations than iron, copper is far more active than iron in catalyzing hydroxy free radical formation via Haber-Weiss pathways.
It is further known that complexes of iron with many chelating agents retain the ability of iron to catalyze hydroxy free radical formation in Haber-Weiss pathways. Iron complexed by the chelator ethylene diamine tetra acetic acid (EDTA) is typically more active in catalyzing free radical formation in Haber-Weiss pathways at near neutral pH than is uncomplexed iron. Iron complexes of N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylene diamine (TPEN) and hydrolyzed forms of 4,4′-(1-methyl-1,2,-ethanediyl)bis-2,6-piperazinedione (Razoxane) also are active in catalyzing free radical formation in Haber-Weiss pathways.
It is also known that zinc cations are co-released with glutamate from synaptosomes of nervous system cells that employ glutamate as a chemical messenger. Normally such zinc released in the nerve synapse is rapidly re-incorporated into synaptosomes. The zinc released from synaptosomes as a result of ischemia, prolonged seizures and brain injury accumulates in the extracellular fluid surrounding nerve cell bodies. When excess zinc enters the cell body, the zinc can initiate cell death by apoptosis and necrosis. Since siderophores such as deferoxamine have low affinity for zinc cations, their use has not unequivocally provided neuroprotection.
It is still further known that metal cations such as Ca+2 that are not first transition series elements perform important functions in the body. Such metal cations can compete with cations of first transition series elements for chelation by a chelator that has a high affinity for Ca+2 and thereby interfere with the chelation of first transition series cations by the chelator. Moreover, chelation of cations such as Ca+2 can impair the normal functions of these cations in the body.